IFN-γ is a cytokine that is involved in pathogenic immunity, and plays an important role in macrophage activation, and in the upregulation of class I and II major histocompatibility complex (MHC) antigens. It is produced by natural killer (NK) T cells, by CD4 T helper 1 (Th1) cells, and also by CD8 cytotoxic T lymphocytes (CTL) effector T cells.
One of the crucial roles of IFN-γ is in immunomodulation and immunostimulation. Autoinflammatory and autoimmune conditions can be associated with overproduction or imbalances in IFN-γ secretion, whilst IFN-γ itself has been used to treat patients with immunodeficiencies such as chronic granulomatous disease. IFN-γ has, for example, been implicated in Alzheimer's disease and prion-related diseases (Bate et al; Journal of Neuroinflammation; 2006, 3:7, doi:10.1186/1742-2094-3-7), multiple sclerosis (Traugott et al; Annals of Neurology, 24(2), 1988, 243-251), and epilepsy (Sinha et al; Epilepsy Research, 2008, 82(2-3), 171-176).
A number of cyclic diazo and triazo compounds have been previously reported as being antifolates, and also voltage dependent sodium channel blockers, for example as described in WO 2008/007149, WO 2009/090431, WO 2011/004195 and WO 2011/004196. Disorders in mammals that are said to be treatable by sodium channel blocking include epilepsy, multiple sclerosis, glaucoma and uveitis, cerebral traumas and cerebral ischemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motor neurone disease, Alzheimers disease, Parkinsons disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood anxiety, cognitive disorders, schizophrenia and trigeminal autonomic cephalalgias. Antifolates can be used to treat mammalian cancers, and can also act as antimalarials against Plasmodium vivax and Plasmodium falciparum malaria, especially in humans.
There remains a need for compounds that can modulate the production of the pro-inflammatory cytokine IFN-γ, so that medical conditions and diseases that are related to its presence or over-production can be treated or controlled.